Recent Advances in the Management of Epilepsy 1) Several new anti-epileptic drugs have been approved by the FDA in recent years including clobazam, oxcarbazepine, and parampanel. 2) Drugs currently in clinical trials include brivaracetam, carisbamate, and NS1209 which aim to decrease neuronal excitation or enhance inhibition. 3) Existing drugs are also being developed in new formulations like intranasal diazepam and applications such as using levetiracetam and rufinamide for additional conditions. Non-pharmacological options are also expanding.

1. RECENT ADVANCES IN
THE MANAGEMENT
OF EPILEPSY
Dr. Karabi Adak
MBBS, MD

2. CORE COMPONENTSOFTHEPRESENTATION
DEFINITION
TYPES
PATHOPHYSIOLOGY
CONVENTIONAL ANTI EPILEPTICS
ANTI EPILEPTICS a/c TO MOA
ANTI EPILEPTICS IN PREGNANCY
RECENT ADVANCES

3. Epilepsy is a collective term for a group of
chronic disorders characterized by recurrent
seizures associated with disturbance of
consciousness and/or a characteristic body
movement (convulsion).
Seizure is a sudden and transient episode
associated with abnormal excessive electrical
discharges from a group of CNS neurons.

4. TYPESOFEPILEPSY
• GENERELISED TONIC CLONIC SEIZURE(
GTCS/GRAND EPILEPSY)
• ABSENCE SEIZURE( PETIT MAL / MINOR
EPILEPSY)
• ATONIC SEIZURE( AKINETIC EPILEPSY)
• MYOCLONIC SEIZURE
• INFANTILE SPASM ( HYPSARRHYTHMIA)
GENERELISED
SEIZURE
• SIMPLE PARTIAL SEIZURE (CORTICAL FOCAL
EPILEPSY)
• COMPLEX PARTIAL SEIZURE (TEMPORAL LOBE
EPILEPSY)
• SPS OR CPS SECONDARILY GENERELISED .
PARTIAL
SEIZURE

7. PATHOPHYSIOLOGY

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9. CONVENTIONAL ANTI EPILEPTICS

10. • Phenobarbitone
1. BARBITURATE
• Primidone
2. DEOXYBARBITURATE
• Phenytoin
• Fosphenytoin
3. HYDANTOIN
• Carbamazepine
• Oxcarbazepine
4. IMINOSTILLBENE
• Ethosuximide
5. SUCCINAMIDE
• Valproic acid
6. ALIPHATIC
CARBOXYLIC ACID

11. • Clonazepam
• Diazepam
• Lorazepam
• Clobazam
7)BENZODIAZEPINES
• Lamotrizine
8)PHENYLTRIAZINE
• Gabapentin
9) CYCLIC GABA
ANALOGUES
• Leveteracetam
• Lacosamide
• Vigabatrin
• Tiagabine
• Topiramate
• Zonisamide
10) NEWER DRUGS

12. ANTI EPILEPTICS ACCORDING TO MECHANISM

13. 1) INHIBITION OF VOLTAGE GATED Na2+ CHANNELS
2) ENHANCEMENT OF GABA ergic ACTION
3) BLOCKADE OF NMDA / AMPA RECEPTORS
4) MODULATORS OF Ca2+ CHANNELS
5)SELECTIVE BINDING TO SYNAPTIC VESICULAR PROTEIN (SV2A)

14. 1) INHIBITIONOFVOLTAGE GATED Na 2+ CHANNELS
• PROLONGS INACTIVATED PHASE OF VOLTAGE GATED Na CHANNELS
AND DELAYS REVERSION TO RESTING PHASE THUS REDUCING
NEURONAL EXCITABILITY
• PHENYTOIN
• CARBAMEZIPINE
• LAMOTRIGINE
• LACOSAMIDE
• RUFINAMIDE
• VALPROATE

15. 2)ENHANCEMENTOFGABAergicACTIONS
BENZODIAZIPINES INCREASES FREQUENCY OF CHLORIDE CHANNELS
OPENING
• PHENOBARBITAL INCREASES DURATION OF OPENING OF CHLORIDE
CHANNELS
• VIGABATRIN IRREVIRSIBLY INHIBITS GABA TRANSMINASE
TIAGABINE / VALPROATE INHIBITS GABA UPTAKE TRANSPORTER
(GAT-1)
VALPROIC ACID ACTIVATES GLUTAMIC ACID DECARBOXYLASE (GAD)

16. 3)BLOCKADEOF NMDA/AMPA RECEPTORS
• NMDA BLOCKER - FELVAMATE
• AMPA BLOCKER -
1) PHENOBARBITAL
2) TOPIRAMATE
3) LAMOTRIGINE
4) PARAMPENEL

17. 4) MODULATORS OFCA 2+CHANNELS
a) CA 2+CHANNEL BLOCKER
• ALL CA2+ CHANNELS ( T TYPE , P TYPE , N TYPE )
ARE BLOCKED BY
b) 𝛼2 δ1 SUBUNIT OF CA CHANNELS
• DECREASES ENTRY OF Ca BY BINDING TO 𝛼2 δ1 LIGAND
1) ETHOSUXIMIDE
2) VALPROIC ACID
3) LAMOTRIGINE
1) GABAPENTIN
2) PREGABILIN

18. 5)SELECTIVE BINDINGTOSYNAPTICVESICULARPROTEIN(SV2A)
• BINDS TO SV2A AND MODULATES GLUTAMATE RELEASE AND GABA
RELEASE
1) LEVATERACETAM
2) BRIVARACETAM

19. COMMONLY EMPLOYED ANTIEPILEPTICS
PHENYTOIN
CARBAMAZEPINE
ETHOSUXIMIDE
VALPROATE
PHENOBARBITONE

20. 1) PHENYTOIN
PHARMACOLOGICAL ACTIONS
1. CNS ACTIONS - not a CNS depressant but
sedation occurs at therapeutic doses
2. CVS ACTIONS – cell membrane
stabilizing effect on the myocardium
ADVERSE EFFECTS
1. AT THERAPEUTIC LEVEL
 Gum hypertrophy
 Hypersensitivity reactions
 Hirsutism
 Megaloblastic anemia
 Osteomalacia
 Hyperglycemia
 Fetal hydantoin syndrome
2. AT HIGH PLASMA LEVELS
 Cerebellar/vestibular
 CNS EFFECTS
 GIT EFFECTS

21. • Slow oral absorption ( but iv causes thrombophlebitis & im causes pain).
• It is 70-95% albumin bound and metabolized by Para hydroxylation in the liver.
• Phenytoin exhibits dose dependent elimination , at low concentration (<10mcg/ml) –
elimination occurs by 1st order kinetics and T1/2 is 10-24 hours.
As the rate of administration increases , metabolizing enzyme gets saturated ,
kinetic changes to 0th order and T1/2 increases to 60 hours
• Therapeutic monitoring of phenytoin is essential for adjustment of dosage.
• Drug interactions –
1. (Phenobarbitone , carbamazepine , warfarin) and phenytoin induces each others
metabolism so unpredictable interaction.
2. Valproate , chloramphenicol, isoniazide , cimetidine decreases the metabolism of
phenytoin
3. Phenytoin increases metabolism of OCP’s , doxycycline , theophylline

22. 2)CARBAMAZEPINE
• This was mainly used for the treatment of trigeminal and related
neuralgias.
• Deafferentation pain of diabetic neuropathy?
• Oral absorption is slow , metabolized by liver
• It’s a potent hepatic microsomal enzyme inducer & accelerates its
own metabolism as well as other drugs.
• Adverse effects –
Dose related neurotoxicity – sedation/dizziness/vertigo/diplopia/ataxia
Acute intoxication causes – coma/convulsions/cardiovascular collapse
Hypersensitivity reactions – rashes/photosensitivity/lupus like
Rarely agranulocytosis/ neutropenia/ aplastic anemia
Water retention/hyponatremia
Fetal malformations

23. • Drug interactions –
Carbamazepine increases hepatic metabolism of OCP, steroids , vit D ,
theophylline , warfarin
Carbamazepine metabolism inhibited by erythromycin , isoniazid , verapamil,
cimetidine, sodium valproate
• Indications other then treatment of seizure –
Trigeminal neuralgia
Diabetes insipidus
Alternative to lithium
Alcohol withdrawal syndrome

24. 3)ETHOSUXIMIDE
• Slowly but Completely absorbed from GIT , 20% excreted unchanged in
urine and rest metabolized in liver.
• Raises seizure threshold and only used in absence seizure but nowadays
suppressed by valproate.
• Adverse actions –
Gi intolerance/tiredness/mood change/agitation/parkinsonism
Hypersensitivity reactions like – rash/SLE
Blood dyscracias are rare
• Does not induce or inhibit liver enzymes

25. 4)VALPROATE
• Broad spectrum anti epileptic which acts on various sites.
• Oral absorption is good , completely metabolised by liver and excreted in urine.
• DOC for absence seizure . Uses other then seizure –
Mania/bipolar illness/panic attacks
Prophylactic efficacy in migraine
• Adverse reactions –
Increased appetite/Vomiting/loose motion/heart burn
Drowsiness/ataxia/tremor
Alopecia/curling of hair/bleeding tendency
Hepatotoxic

26. • Drug interactions –
Valproate inhibits metabolism of
phenobarbitone/lamotrigine/phenytoin/carbamazepine
Seizure precipitates on concurrent administration of clonazepam and valproate
Fetal abnormalities are more common with valproate and carbamazepine
concurrent use.

27. 5)PHENOBARBITONE
• Slow oral absorption , metabolised in liver as well as excreted
unchanged by kidney.
• It has a wide anti epileptic spectrum but became less popular due to its
dulling and behavioural side effects
• Adverse reactions
Major drawback is its sedating effect
Long term use may produce behavioural abnormalities/diminution of
intelligence/impairment of learning and memory/hyperactivity in
children/mental confusion in elderly
Nystagmus/ataxia
Connective tissue abnormality – frozen shoulder

28. 6)GABAPENTIN
• Well absorbed orally , not protein bound , does not get metabolized ,
excreted unchanged in urine , t1/2 of 5-9 hrs.
• Concurrent use of it does not affect blood levels of other AED.
• Apart from its use as AED , its useful in treating diabetic neuropathy , post
herpetic neuralgia , trigeminal neuralgia .
• Adverse effects –
Drowsiness , ataxia , dizziness
Fatigue , weight gain

30. DRUGSDECRESINGTHRESHOLDOFSEIZURE
• Sympathomimetics – epherdrine , amphetamine , cocaine
• Some tricyclic antidepressants – amitriptyline , imipramine , doxepin
• Lithium , flumazenil
• Withdrawal of alcohol / short acting barbiturates/benzodiazepines
• Anesthetic agents - ether , halothane , lignocaine
• Analgesics -tramadol , pethidine
• Antimicrobials - penicillins , cephalosporins
• Immunomodulators – methotrexate , cyclosporine

31. ANTI EPILEPTICS AND PREGNANCY

32. • AED should not be stopped abruptly during pregnancy, instead should be reduced to
minimum.
• 90% of women taking antiepileptics give birth to healthy babies & pregnancy need
not be terminated.
• Issues include interaction with OCP , potential teratogenic effect , effects on vit k
metabolism.
• Major fetal malformation – cardiac defects , cleft palate , neural tube defects , spina
bifida occurs in 2% pregnancies in AED.
• Other pregnancy related complications are – toxemia , intrapartum hemorrhage , pre
mature labor
• Minor malformations – nail hypoplasia, low set ears , prominent lips might also occur

33. • AED ‘s can promote hemorrhagic diasthesis in the neonate , thus they
should receive vit k at birth.
• Even treatment with vit k 10mg/day during the last month of
gestation has been recommended for prophylaxis to reduce
coagulopathy and intra cerebral hemorrhage in the neonate .

34. MAGNESIUMSULPHATE
• Although not used as anti epileptic drug , it is preferred as DOC to
prevent convulsions of eclampsia and severe pre eclampsia of
pregnancy .
• Though MOA is not clear , it reduces cardiac and smooth muscle
activity and lowers blood pressure which benefits pre eclamptic pt.
• Pre eclampsia may progress to eclampsia which is a convulsive phase
where use of conventional anti epileptic drug is usually avoided due to
teratogenic effects

35. Mx of STATUS EPILEPTICUS

36. RECENT ADVANCES IN THE
MANAGEMENT OF EPILEPSY

37. 1) FDA approved drugs
2) Drugs in pipeline
3) New formulations
4) New applications of existing drugs

38. FDA approved drugs

39. 1) CLOBAZAM
• Acts by potentiation of GABAergic transmission via binding to GABA –
A receptors
• It has lower tendency to produce sedation
• FDA approved on 2011 oct

40. 2) OXCARBAZEPINE
• Acts by blockade of voltage sensitive sodium channels
• FDA approved in oct 2012 approved ones a day formulation for adults
and children> 6yrs
• Adverse effects include headache , dizziness , diplopia
• Rare and serious adverse effects are hyponatremia and suicidal
ideation

41. 3) PARAMPANEL
• A highly selective non competitive AMPA type glutamate receptor
antagonist
• FDA approved in nov 2021 , for partial onset seizure in patients>12
years
• Adverse effects include dizziness , fatigue , irritability ,
neuropsychiatric events

42. 4)TOPIRAMATE
• Blockage of voltage dependent sodium channels
• Augmentation of activity of neurotransmitter GABA
• Antagonism of AMPA
• March 2014 – US FDA approved
• As monotherapy and adjunctive therapy associated with lennox gestaut
syndrome

43. DRUGS IN PIPELINE

44. 1) DRUGS DECRESING NEURONAL
EXCITATION
2)DRUGS ENHANCING NEURONAL
INHIBITION
• Blockade of sodium channels –
a) Brivaracetam
b) Carisbamate
• Inhibition of glutamate release/AMPA
antagonist
a) NS 1209
b) BGG 492
• Stiripentol

45. 1) BRIVARACETAM
• Levetiracetam analogue
• Sodium channel blocking properties
• Currently in phase III for partial onset seizure

46. 2) CARISBAMATE
• Novel neuromodulator
• Inhibits voltage gated sodium & calcium channels
• Phase II study for adjunctive use in partial onset seizures

47. 3) AMPA ANTAGONIST

48. 4) STIRIPENTOL
• Increases GABA levels in brain tissue
• In phase III trial for childhood focal seizure

49. NEW FORMULATIONS

50. INTRANASAL
• Diazepam
• Midazolam
DIAZEPAM AUTO INJECTIONS

53. NEW APPLICATIONS OF
EXISTING DRUGS

54. 1) LEVETIRACETAM

55. 2) RUFINAMIDE

56. 3) LACOSAMIDE

58. NONPHARMACOLOGICALAPPROACH TOTREATSEIZURES
1. Vagus nerve stimulation has been recently approved by FDA to treat
partial complex seizure with/without secondary generalizations.
2. Prescribing ketogenic diet for treatment of childhood epilepsy.
3. Upcoming modalities –
i. Stereotactic radiosurgery
ii. Laser thermablation
iii. Deep brain stimulation

59. References :
1. “Essentials of medical pharmacology” by K. D. Tripathi
2. Ritter, J. (2020). Rang and Dale's pharmacology (Ninth edition.).
3. Pharmacology and pharmacotherapeutics - Satoskar
4. Goodman & Gilman's: The Pharmacological Basis of Therapeutics
5. Google images
6. Google scholar

60. THANKYOU